Method for treating neovascularization

ABSTRACT

The present invention describes an improved photodynamic treatment to treat subfoveal choroidal neovascularization (CNV).

This application claims priority under 35 U.S.C. § 119(e) fromprovisional patent application Ser. No. 60/191,807, filed Mar. 24, 2000,the entire disclosure of which is incorporated by reference herein inits entirety.

FIELD OF THE INVENTION

The invention relates to an improved method to treat ocularneovascularization, such as subfoveal choroidal neovascularization (CNV)by use of an anti-angiogenic agent as an adjunct to photodynamic therapy(PDT).

BACKGROUND OF THE INVENTION

The present treatment of age related macular degeneration (AMD) withphotodynamic therapy using an appropriate photosensitive agent leads toexcellent short-term results for treating CNV and is a significantimprovement over laser photocoagulation. However, it has beendemonstrated that in patients treated with PDT there can be a recurrenceof choroidal neovascularization within the treatment area and/ordevelopment of new lesions outside the original lesions (so calledprogression) such that repeated PDT is required. Therefore a treatmentregimen which could be used in conjunction with PDT, and which wouldprevent the growth of new vessels, would be advantageous for thetreatment of CNV. The prevention of new, unwanted neovasculature couldreduce the number of PDT treatments required in some subjects. Themethods of the invention can also be used to treat other types of oculartissue afflicted with neovascularization, such as retinal neovascularlesions due to, e.g., diabetes.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a method for treatingunwanted neovasculature in a subject, comprising:

-   (a) administering an effective amount of an anti-angiogenic agent to    the subject;-   (b) administering an effective amount of a photosensitive agent to    the subject; and-   (c) irradiating the unwanted neovasculature with light having a    wavelength absorbable by the photosensitive agent.

In another aspect, the invention relates to a kit comprising at leastone anti-angiogenic agent and at least one photosensitive agent.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that administration of an anti-angiogenic can beused in conjunction with PDT for the treatment of a subject havingunwanted ocular neovasculature, e.g. CNV.

PDT as a treatment is well known in the art, and generally involves theuse of a photosensitive agent activated by a laser. Preferred methodsand compositions for PDT treatment of neovascularization utilizing aphotosensitive agent and laser treatment is disclosed in U.S. Pat. Nos.4,920,143; 5,095,030; 5,214,036; 5,707,608; 6,074,666; 5,770,619;5,798,349; 5,756,541; 4,883,790; and 5,283,255, all of which areexpressly incorporated by reference herein in their entirety. When PDTis employed to treat ocular neovascularization, the photosensitive agentlodges in the ocular tissue affected by neovascularization (i.e., thetarget ocular tissue) and is activated by a laser having a wavelengthabsorbable by the photosensitive agent. In the present invention, ananti-angiogenic agent is administered before, after and/orsimultaneously with the photosensitive agent used in the PDT treatment.The combination of PDT and anti-angiogenic agent is referred to hereinas “adjunctive PDT”.

As used herein, the term “in conjunction with” is to be construed asadministration of an anti-angiogenic agent to a subject eithersequentially or simultaneously with a photosensitive agent, with thepreferred method being sequential administration. As an example ofsequential treatment, an anti-angiogenic agent may be administeredbetween about 0 and about 4 weeks, more preferably between about 0.5 andabout 1.5 weeks, before administration of the photosensitive agent. Inan alternative sequential treatment, the anti-angiogenic agent may beadministered between about 0 and about 4 weeks, more preferably betweenabout 0 and about 1 week, after administration of the photosensitiveagent. If necessary, the anti-angiogenic agent may be sequentiallyadministered both before and after PDT according to the scheduledescribed above. Alternatively, the treatment is considered simultaneousif the anti-angiogenic is co-administered with the photosensitive agent.Particular subjects may require multiple adjunctive PDT treatments.Particular adjunctive PDT treatments may require multipleadministrations of the anti-angiogenic agent before PDT, multipleadministrations of anti-angiogenic agent after PDT, or both.

Anti-angiogenic agents, as the term is used herein, mean agents thatwork by preventing, inhibiting or reversing the growth of new bloodvessels via the process commonly known as angiogenesis. Examples ofanti-angiogenic agents useful in adjunctive PDT include staurosporins,for example N-benzoyl-staurosporine, somatostatins, such as octreotide

and steroids, such as triamcinolone. Other anti-angiogenic agents usefulin the present invention are VEGF inhibitors, such as CGP 79987D, CGP 57148B or CGP 53 716,

and the like. These anti-angiogenic agents are particularly useful toinhibit the recurrence, re-opening, development and/or progression ofblood vessel growth that occurs during choroidal neovascularization, andoffer significant benefits in adjunctive PDT.

Preferred anti-angiogenic agents are inhibitors of protein kinase C(PKC) (e.g., N-benzoyl-staurosporine), antagonists of growth hormone andIGF-1 (e.g., octreotide), antagonists of vascular endothelial growthfactor (VEGF) (e.g., CGP 79787, N-benzoyl-staurosporine, CAM 781),inhibitors of cyclooxygenase II (e.g., diclofenac, rofecoxib, celecoxib,and the like), antagonists of angiotensin II (e.g., valsartan),antagonists of NF-kappa B, and PLA2 antagonists. More preferredanti-angiogenic agents are PKC inhibitors, VEGF antagonists andantagonists of growth hormone and IGF-1.

Most preferred anti-angiogenic agents are inhibitors of PKC andantagonists of VEGF, in particular inhibitors of PKC, such asN-benzoyl-staurosporine, CGP 79787, and octreotide. Particularlypreferred is N-benzoyl-staurosporine.

Preferred photosensitive agents are the chlorins, bacteriochlorins,phthalocyanines, porphyrins, purpurins, merocyanines, pheophorbides andpsoralens.

Highly preferred photosensitive agents are the porphyrins and is mostpreferably the a green porphyrin, in particular benzoporphyrinderivative monoacid ring A (“BPD-MA”).

Any of the photosensitive compounds described above can be used in themethods of the invention. Of course, mixtures of two or morephotosensitive compounds can also be used; however, the effectiveness ofthe treatment depends on the absorption of light by the photosensitivecompound so that if mixtures are used, components with similarabsorption maxima are preferred.

The nature of the formulation used to deliver the anti-angiogenic agentor photosensitive agent will depend in part on the mode ofadministration and on the nature of the anti-angiogenic agent and thephotosensitive agent selected. Any pharmaceutically acceptableexcipient, or combination thereof, appropriate to the particular activecompounds may be used. Thus, the photosensitive agents oranti-angiogenic compounds may be administered as an aqueous composition,as a transmucosal or transdermal composition, as a subtenons orintraocular injection or in an oral formulation. The formulation mayalso include liposomes. Liposomal compositions are particularlypreferred especially where the photosensitive agent is a greenporphyrin. The anti-angiogenic agent is preferably administered via anaqueous carrier.

The above mentioned anti-angiogenic agents can be administered in any ofa wide variety of ways, for example, orally, parenterally, or rectally,or the compound may be placed directly in or on the eye. Parenteraladministration, such as intravenous, intramuscular, or subcutaneous, ispreferred for the photosensitive agent. Intravenous injection isespecially preferred. Oral administration or ocular administration ispreferred for administration of the anti-angiogenic agent.

The dose of the above compounds can vary widely depending upon the modeof administration; the formulation in which it is carried, such as inthe form of liposomes, or whether it is coupled to a target-specificligand, such as an antibody or an immunologically active fragment. As isgenerally recognized, there is a nexus between the type ofphotosensitive agent, the formulation, the mode of administration, andthe dosage level. The anti-antigenic agent is administered in a mannerand amount sufficient to effect agent interaction with the unwantedneovasculature. The photosensitive agent is administered in an amounteffective to close or eradicate the unwanted neovasculature uponirradiation with light of the appropriate wavelength.

While various photoactive compounds require different dosage ranges, ifgreen porphyrins are used, a typical dosage is of the range of 0.1-50mg/m² of body surface area, preferably from about 1-10 mg/m² and evenmore preferably about 2-8 mg/m².

While various anti-angiogenic compounds require different dosage ranges,a typical dosage is of the range of 1-500 mg/kg of body weight,preferably from about 10-250 mg/kg of body weight.

The irradiation (laser power, irradiation duration) is carried out inaccordance to methods known in the art as mentioned above, for examplein accordance to the light treatment protocols set out in U.S. Pat. Nos.5,770,619; 5,798,349; 5,756,541; 4,883,790; and 5,283,255.

Kits that contain an anti-angiogenic agent and a photosensitive agentare also within the scope of the invention. Such kits can also containsuitable vehicles for the reconstitution or administration of theaforesaid anti-angiogenic agents as well as devices for theadministration of such agents.

1: A method for treating unwanted ocular neovasculature in a subjectsuffering from choroidal neovascularization or retinalneovascularization, the method comprising; (a) administering aneffective amount of an anti-angiogenic agent to the subject, wherein theanti-angiogenic agent is selected from the group consisting ofinhibitors of protein kinase C, antagonists of growth hormone,antagonists of IGF-1. antagonists of vascular endothelial growth factor,antagonists of angiotensin II, antagonists of NF-kappa B, andphospholipase A2 antagonists; (b) administering an effective amount of aphotosensitive agent to the subject; and (c) irradiating the unwantedneovasculature with light having a wavelength absorbable by thephotosensitive agent. 2: The method of claim 1, wherein theanti-angiogenic agent is administered between about 0 and about 4 weeksbefore the administration of the photosensitive agent. 3: The method ofclaim 1, wherein the anti-angiogenic agent and the photosensitive agentare administered simultaneously. 4: The method of claim 1, wherein theanti-angiogenic agent is administered between about 0 and about 4 weeksafter the administration of the photosensitive agent. 5: The method ofclaim 1, wherein the anti-angiogenic agent is administered between about0 and about 4 weeks before the administration of the photosensitiveagent and between about 0 and about 4 weeks after the administration ofthe photosensitive agent.
 6. (canceled) 7: The method of claim 1,wherein the anti-angiogenic agent is selected from the group consistingof inhibitors of protein kinase C and antagonists of vascularendothelial growth factor. 8: The method of claim 7, wherein theanti-angiogenic agent is an inhibitor of protein kinase C. 9: The methodof claim 7, wherein the anti-angiogenic agent is selected from the groupconsisting of N-benzoyl-staurosporine, CGP 79787, and octreotide. 10:The method of claim 9, wherein the anti-angiogenic agent isN-benzoyl-staurosporine. 11: The method of claim 1, wherein thephotosensitive agent is selected from the group consisting of aporphyrin and a purpurin. 12: The method of claim 11, wherein thephotosensitive agent is benzoporphyrin derivative monacid ring A. 13:The method of claim 2, wherein multiple administrations ofanti-angiogenic agent are performed prior to the administration of thephotosensitive agent. 14: The method of claim 4, wherein multipleadministrations of anti-angiogenic agent are performed after theadministration of the photosensitive agent. 15: The method of claim 5,wherein multiple administrations of anti-angiogenic agent are performedprior to the administration of the photosensitive agent and whereinmultiple administrations of anti-angiogenic agent are performed afterthe administration of the photosensitive agent. 16-19. (canceled) 20:The method of claim 9, wherein the anti-angiogenic agent is CGP 79787.21: The method of claim 9, wherein the anti-angiogenic agent isoctreotide.